LETTER
Synthesis of N-Acetyl-1,3-dimethyltetrahydroisoquinolines
2067
D. W.; Pandey, A.; Lawson, J. A.; Dawson, M. I. J. Hetero-
The organic extracts were combined, filtered through alu-
mina to remove traces of Hg, dried (MgSO4) and evaporated
in vacuo. Preparative layer chromatography on silica gel
(EtOAc–hexane–aq NH4OH, 66:33:1) afforded the 1,3-
trans-dimethyl cyclized product 3 (0.11 g, 56%) as a light
yellow oil.
cycl. Chem. 1996, 33, 1371. (h) de Koning, C. B.; Michael,
J. P.; van Otterlo, W. A. L. Tetrahedron Lett. 1999, 40,
3037. (i) de Koning, C. B.; Michael, J. P.; van Otterlo, W. A.
L. J. Chem. Soc., Perkin Trans. 1 2000, 799.
(5) (a) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen, J. R.;
Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877.
(b) Hoye, T. R.; Chen, M. Tetrahedron Lett. 1996, 37, 3099.
(c) Watanabe, T.; Uemura, M. Chem. Commun. 1998, 871.
(6) Bringmann, G.; Götz, R.; Harmsen, S.; Holenz, J.; Walter, R.
Liebigs Ann. Chem. 1996, 2045.
(7) Toda, J.; Matsumoto, S.; Saitoh, T.; Sano, T. Chem. Pharm.
Bull. 2000, 48, 91.
(8) This work is taken from the PhD thesis of W. A. L. van
Otterlo, University of the Witwatersrand, 1999.
(17) The product 3 showed two distinct sets of signals in its 1H
NMR spectrum, indicating rotamers about the amide C–N
bond. Spectroscopic Data for 3. 1H NMR (400 MHz;
CDCl3): = 7.43–7.32 (10 H, m, 10 PhH), 6.44 (1 H, s,
7-H), 6.43 (1 H, s, 7-H), 5.50 (1 H, q, J = 6.4 Hz, 1-H), 5.16
(1 H, q, J = 6.6 Hz, 1-H), 4.95–4.86 (4 H, m, 2 OCH2),
4.68–4.62 (1 H, m, 3-H), 4.23–4.15 (1 H, m, 3-H), 3.91 (6 H,
s, 2 OCH3), 3.86 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 2.99
(2 H, dd, J = 15.2 and 2.4 Hz, 4-H pseudo-equatorial), 2.64–
2.54 (2 H, m, 2 4-H pseudo-axial), 2.24 (3 H, s, COCH3),
2.17 (3 H, s, COCH3), 1.28 (6 H, d, J = 6.6 Hz, 2 1-CH3),
0.84 (3 H, d, J = 6.2 Hz, 3-CH3), 0.83 (3 H, d, J = 6.1 Hz,
3-CH3); 13C NMR (50.32 MHz; CDCl3): = 170.0, 169.7 (2
NCOCH3), 151.9, 151.5, 151.4, 150.7, 138.9, 139.0 (6
ArC–O), 137.6, 137.5, 129.0 (3 ArC–C), 128.5, 128.5,
128.3, 128.0 (4 PhC), 119.5, 118.6 (2 ArC–C), 95.2, 94.9
(2 7-C), 75.2 (OCH2), 55.9, 55.6, 55.6 (3 OCH3), 49.1,
46.7 (2 1-C), 46.3, 44.4 (2 3-C), 28.6, 27.8 (2 4-C),
23.3, 22.3, 22.3, 21.3, 20.9, 19.2 (6 CH3). IR (thin film):
max = 2820 m (C–H st, OCH3), 1635 vs (C=O st), 1583 m
(ArC = C st) cm–1; MS (EI): m/z = M+ 369.1931 (C22H27NO4
requires 369.1940), 369 (M+, 20%) 354(83), 278(95),
263(9), 219(78), 193(100), 91(34), 43(16).
(9) (a) Kametani, T. In The Total Synthesis of Natural Products,
Vol. 3; ApSimon, J., Ed.; John Wiley and Sons, Inc.: New
York, 1977, 1–272. (b) Rozwadowska, M. D. Heterocycles
1994, 39, 903.
(10) (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc.
1972, 94, 679. (b) A review: Mitsunobu, O. Synthesis 1981,
1. (c) See also: Hughes, D. L. Org. React. 1992, 42, 335.
(11) Wolfe, S.; Hasan, S. K. Can. J. Chem. 1970, 48, 3572.
(12) Spectroscopic Data for 4. 1H NMR (400 MHz; CDCl3):
7.47–7.26 (5 H, m, 5 PhH), 6.79 (1 H, br d, J = 9.3 Hz,
=
NH), 6.49 (1 H, s, 5-H), 6.01–5.93 (1 H, m, 2 -H), 5.46–5.42
(1 H, m, CHCH3), 5.02–4.85 (2 H, m, 3 -H), 4.91 (1 H, d,
J = 10.8 Hz, OCH2), 4.86 (1 H, d, J = 10.8, OCH2), 3.90 (3
H, s, OCH3), 3.87 (3 H, s, OCH3), 3.64–3.63 (2 H, m, 1 -H),
1.92 (3 H, s, COCH3), 1.40 (3 H, d, J = 6.9 Hz, CHCH3). 13
C
Heating compound 3 in an NMR tube in toluene-d8 up to
90 °C resulted in coalescence of the two sets of signals.
NMR (100.63 MHz; CDCl3): = 168.4 (C=O), 154.4, 152.1,
140.2 (3 ArC–O), 137.9 (ArC–C), 136.9 (2 –C), 132.5
(ArC–C), 128.2, 127.8, 127.6 (3 PhC), 122.2 (ArC–C),
115.4 (3′–C), 96.2 (5-C), 74.9 (OCH2), 55.9, 55.6 (2
OCH3), 43.7 (CHCH3), 30.7 (1 -C), 23.6 (COCH3), 20.9
(CHCH3). IR (thin film): max = 3331 br (N–H st), 2876 m
(C–H st, O–CH2), 2837 m (C–H st, O–CH3), 1637 vs (C=O
st), 1597 (ArC=C st) cm–1; MS (EI): m/z = M+ 369.1933
(C22H27NO4 requires 369.1940), 369 (M+, 14%) 326(1),
278(77), 219(86) 204(16), 193(84), 189(16), 91(40), 43(16).
(13) Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Chem. Soc., Perkin
Trans. 1 1981, 1197.
Characteristic chemical shifts in the 1H NMR spectrum:
2.99 ppm (doublet of doublets, J = 15.2 and 2.4 Hz) and
2.64–2.54 ppm (multiplet) for the pseudo-equatorial and
=
=
pseudo-axial protons at C-4 respectively. Four sets of signals
corresponding to the two protons at C-1 and C-3 were also
clearly visible as quartets at = 5.50 (J = 6.4 Hz) and 5.16
(J = 6.6 Hz) ppm and as multiplets at = 4.68–4.62 and
4.23–4.15 ppm respectively. The 13C NMR spectrum also
showed two characteristic sets of resonances: at = 49.1 and
46.7 (C-1) ppm, = 46.3 and 44.4 (C-3) ppm and = 28.6
and 27.8 (C-4) ppm.
(14) (a) Larock, R. C. In Solvomercuration/Demercuration
Reactions in Organic Synthesis; Springer-Verlag: Berlin,
1986, Chap. VI, 443–521. (b) Larock, R. C. In
(18) Example of rotational isomers in tetrahydroisoquinolines
due to N-acetyl and N-formyl substituents: Bringmann, G.;
Holenz, J.; Wiesen, B.; Nugroho, B. W.; Proksch, P. J. Nat.
Prod. 1997, 60, 342.
(19) de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L.,
unpublished results.
(20) For isomer 3, the C-1 methyl substituent showed an NOE
with the H-4 pseudo-axial proton, indicating that the C-1
methyl substituent must be pseudo-axial. For the cis-isomer
9 the same NOE was seen, as well as an NOE between the 1-
methyl and 3-methyl substituents, thereby fixing the cis-
arrangement. Therefore in isomer 3 the C-1 methyl and C-3
methyl groups must be trans.
Comprehensive Organometallic Chemistry II, Vol. 11;
McKillop, A., Ed.; Elsevier Science Ltd.: Amsterdam, 1995,
Chap. 9, 389–459. (c) Wilson, S. R.; Sawicki, R. A. J. Org.
Chem. 1979, 44, 330. (d) Barluenga, J.; Jimènez, C.; Nájera,
C.; Yus, M. J. Chem. Soc., Chem. Commun. 1981, 670.
(e) Takahata, H.; Bandoh, H.; Momose, T. Heterocyles
1995, 41, 1797.
(15) For a related example using PhSeCl see: Clive, D. C. L.;
Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen,
S. M. J. Org. Chem. 1980, 45, 2120.
(16) Hg(OAc)2 (0.27 g, 0.85 mmol, 1.5 mol equiv) was added to
amide 4 (0.19 g, 0.51 mmol) dissolved in THF (10 cm3). The
yellow mixture was then stirred, in the dark, under argon for
21 h at 25 ºC. A further portion of Hg(OAc)2 (0.18 g, 0.51
mmol, 1 mol equiv) was added and the mixture was stirred
for a further 18 h. A mixture of NaBH4 (0.049 g, 1.3 mmol,
2.5 mol equiv) in aq NaOH (5 cm3, 2.5 M) was then added
whilst stirring. After stirring for a further 1 h a sat. aq
Na2CO3 solution (5 cm3) was added and the mixture was
stirred for 20 min. The reaction was allowed to stand for 30
min and the THF was removed under reduced pressure. Sat.
brine solution (10 cm3) and Et2O (10 cm3) were added and
the mixture was extracted with diethyl ether (3 10 cm3).
(21) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(22) NaH (60% in oil, 0.03 g, 0.86 mmol, 10 mol equiv) was
added to mesylate 8 (0.040 g, 0.086 mmol), dissolved in
anhyd THF (10 cm3), under an argon atmosphere. The
reaction mixture was stirred for 18 h, after which the mixture
was cooled to 0 ºC. Water (10 cm3) was added dropwise and
the mixture was extracted with diethyl ether (2 10 cm3).
The organic solvent was washed with brine (10 cm3), dried
and concentrated in vacuo. Preparative layer chromato-
graphy on silica gel (EtOAc–hexane–aq NH4OH, 66:33:1)
afforded an equimolar mixture of the 1,3-trans-dimethyl
product 3, its 1,3-cis-dimethyl isomer 9 (0.027 g, 85%) as
rotamers about the N–Ac bond.
Synlett 2002, No. 12, 2065–2067 ISSN 0936-5214 © Thieme Stuttgart · New York